Project Summary Over 30 years ago it was discovered that cancer cells show a unique metabolic requirement for methionine that separates them from normal cells. This phenomenon is called ?methionine dependence of cancer? or ?methionine sensitivity of cancer? and describes the growth behavior of cancer cells when methionine is replaced with its immediate metabolic precursor homocysteine. While non-tumorigenic cells proliferate at normal rates in homocysteine medium, the overwhelming majority of cancer cells induces cell cycle arrest followed by apoptosis when cultured in homocysteine conditions. While conversion of homocysteine to methionine is not defective in cancer cells, these growth conditions appear to reduce the flux through the one-carbon cycle, which seems to primarily affect cancer cell growth. The dependence on high metabolic flux through methionine metabolism is also observed in solid tumors and leukemias. While the phenomenon of methionine sensitivity of cancer promises great therapeutic potential, it has been difficult to sufficiently reduce methionine availability in patients to trigger tumor regression through dietary restrictions alone. It is thus essential to understand the underlying mechanisms that govern methionine dependence of cancer. We therefore respond to the NCI?s provocative question 11 (Through what mechanisms do diet and nutritional interventions affect the response to cancer treatment?) and aim to understand molecular mechanisms that trigger methionine sensitivity of cancer, and discover treatment modalities that are enhanced by reduced methionine availability.